Nuclear COMMD1 Is Associated with Cisplatin Sensitivity in Ovarian Cancer

Copper metabolism MURR1 domain 1 (COMMD1) protein is a multifunctional protein, and its expression has been correlated with patients’ survival in different types of cancer. In vitro studies revealed that COMMD1 plays a role in sensitizing cancer cell lines to cisplatin, however, the mechanism and its role in platinum sensitivity in cancer has yet to be established. We evaluated the role of COMMD1 in cisplatin sensitivity in A2780 ovarian cancer cells and the relation between COMMD1 expression and response to platinum-based therapy in advanced stage high-grade serous ovarian cancer (HGSOC) patients. We found that elevation of nuclear COMMD1 expression sensitized A2780 ovarian cancer cells to cisplatin-mediated cytotoxicity. This was accompanied by a more effective G2/M checkpoint, and decreased protein expression of the DNA repair gene BRCA1, and the apoptosis inhibitor BCL2. Furthermore, COMMD1 expression was immunohistochemically analyzed in two tissue micro-arrays (TMAs), representing a historical cohort and a randomized clinical trial-based cohort of advanced stage HGSOC tumor specimens. Expression of COMMD1 was observed in all ovarian cancer samples, however, specifically nuclear expression of COMMD1 was only observed in a subset of ovarian cancers. In our historical cohort, nuclear COMMD1 expression was associated with an improved response to chemotherapy (OR = 0.167; P = 0.038), although this association could not be confirmed in the second cohort, likely due to sample size. Taken together, these results suggest that nuclear expression of COMMD1 sensitize ovarian cancer to cisplatin, possibly by modulating the G2/M checkpoint and through controlling expression of genes involved in DNA repair and apoptosis.

铜代谢MURR1结构域1（Copper metabolism MURR1 domain 1, COMMD1）蛋白是一种多功能蛋白，其表达水平与多种癌症患者的生存预后密切相关。体外研究显示，COMMD1可增强癌细胞株对顺铂（cisplatin）的敏感性，但其在癌症铂类化疗敏感性中的作用及具体分子机制仍有待阐明。本研究评估了COMMD1在A2780卵巢癌细胞顺铂敏感性中的作用，以及晚期高级别浆液性卵巢癌（high-grade serous ovarian cancer, HGSOC）患者中COMMD1表达与铂类化疗响应的相关性。研究发现，细胞核COMMD1表达上调可增强A2780卵巢癌细胞对顺铂介导的细胞毒性的敏感性，这一效应伴随更有效的G2/M细胞周期检验点调控，以及DNA修复基因BRCA1与凋亡抑制因子BCL2的蛋白表达水平下调。此外，本研究采用两种组织微阵列（tissue micro-arrays, TMAs）对COMMD1的表达进行免疫组化分析，这两种阵列分别对应晚期HGSOC肿瘤标本的历史性队列及基于随机临床试验的队列。所有卵巢癌样本中均检测到COMMD1表达，但仅在部分卵巢癌组织中观察到特异性细胞核COMMD1表达。在历史性队列中，细胞核COMMD1表达与化疗响应改善显著相关（优势比OR=0.167；P=0.038），但这一关联在第二个队列中未得到验证，推测可能与样本量较小有关。综上，本研究结果表明，细胞核COMMD1表达可增强卵巢癌对顺铂的敏感性，其潜在机制可能通过调控G2/M细胞周期检验点，并通过调控DNA修复与凋亡相关基因的表达实现。